Calcium channel CACNB1 in T cell function and immunity

钙通道 CACNB1 在 T 细胞功能和免疫中的作用

基本信息

批准号：
9811165
负责人：
STEFAN FESKE
金额：
$ 16.95万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2021-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9811165
关键词：
Adoptive Transfer Affect Antibodies Antibody Affinity Antiviral Agents Apoptosis Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Biological Brain CD4 Positive T Lymphocytes Calcium Calcium Channel Calcium Signaling Cardiac Myocytes Cell membrane Cell physiology Cells Clonal Expansion Colitis Complex Coupling Custom Data Disease Disputes Electric Stimulation Genes Genetic study Goals Growth Guide RNA Heart Helper-Inducer T-Lymphocyte Homeostasis Image Immune Immune response Immunity Immunoglobulin G Immunoglobulin M In Vitro Infection Inflammation Ion Channel Knockout Mice Leukocytes Libraries Light Lymphocyte Function Lymphocytic choriomeningitis virus Measurement Mediating Membrane Methods Movement Mus Mutation Neurons Physiological Play Production Proliferation Marker Proteins Reagent Reporting Research Rheumatoid Arthritis Role Signal Transduction Signaling Molecule Spleen Splenocyte Structure of germinal center of lymph node T cell response T cell therapy T-Cell Activation T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymus Gland Transgenic Organisms Validation Viral Virus Virus Diseases antiviral immunity cell mediated immune response cytokine experimental study functional genomics in vivo insight knock-down migration mutant neutralizing antibody new therapeutic target novel response retroviral transduction small hairpin RNA small molecule targeted treatment tool trafficking transmission process tumor voltage voltage gated channel

项目摘要

Project Summary The goal of this project is to determine the role of a poorly studied calcium channel subunit in T lymphocytes (T cells) and immune responses. T cells are white blood cells that play a critical role during viral infection by killing virus-infected cells and promoting the production of virus-neutralizing antibodies. The function of T cells depends on calcium channels that form pores in the cell membrane and facilitate the influx of calcium into cells. Inside cells, calcium functions as a signaling molecule that binds to various proteins and promotes the activation of T cells, for instance by regulating the expression of immune modulatory genes. Our lab has extensively studied the function of calcium channels called CRAC channels that are encoded by ORAI and STIM genes. Recent reports suggest that other calcium channels may also mediate calcium influx and T cell function. Among those channels are voltage-gated calcium channels, which are well studied in the heart and brain where they regulate cell function in response to electrical stimulation. The gene studied in this proposal is CACNB1, which encodes one of four known regulatory subunits of voltage-gated calcium channels. CACNB1 is critical for different aspects of channel function including channel trafficking, activation and inactivation. Past research on CACNB1 has focused on excitable cells such as neurons, but CACNB1 is also expressed in T cells, where its role in immune responses remains unknown. Recently, genetic studies of two pore-forming subunits of voltage-gated calcium channels and several regulatory subunits have shown altered function of T cells that lack these channel subunits or express mutant forms. In particular, mutation of the regulatory CACNB2, B3 and B4 genes were reported to affect T cells development in the thymus and homeostasis in the spleen. The role of CACNB1 in T cells has not been investigated yet although it is the most highly expressed of the four regulatory subunits in T cells. Overall, the role of voltage-gated calcium channels in T cells and immune responses remains disputed, which in part is due to their unclear activation mechanism in T cells, which are not electrically excitable. We recently identified CACNB1 in a functional genomics screen in live mice as one of several ion channels that regulates the growth of T cells in response to viral infection of mice. In this application, we propose to further characterize the role of CACNB1 in T cell function and immune responses. Specifically, we will study how deletion of CACNB1 affects calcium signaling, calcium channel function and the ability of T cells to grow, produce immune modulatory cytokines and kill virus-infected cells. Furthermore, we will investigate the consequences of CACNB1 deficiency for immunity to infection by infecting mice whose T cells lack CACNB1 with viruses and analyzing their immune responses. The proposed research will shed new light on the function of CACNB1 and voltage-gated calcium channels in T cells and immune responses. CACNB1 is the most highly and specifically expressed regulatory subunit in T cells and may represent a new drug target for the treatment of autoimmunity and inflammation.

项目概要该项目的目标是确定 T 淋巴细胞（T 淋巴细胞）中研究不足的钙通道亚基的作用。细胞）和免疫反应。 T 细胞是白细胞，在病毒感染过程中通过杀死病毒发挥着关键作用。病毒感染的细胞并促进病毒中和抗体的产生。 T细胞的功能依赖于在细胞膜上形成孔并促进钙流入的钙通道细胞。在细胞内部，钙充当信号分子，与各种蛋白质结合并促进 T 细胞的激活，例如通过调节免疫调节基因的表达。我们实验室有广泛研究了由 ORAI 编码的称为 CRAC 通道的钙通道的功能， STIM 基因。最近的报告表明其他钙通道也可能介导钙流入和 T 细胞功能。这些通道中包括电压门控钙通道，该通道在心脏和心脏中得到了充分研究。它们在大脑中响应电刺激来调节细胞功能。本提案中研究的基因是 CACNB1，编码电压门控钙通道的四个已知调节亚基之一。 CACNB1 对于通道功能的不同方面（包括通道交易、激活和失活）至关重要。过去的对CACNB1的研究主要集中在神经元等可兴奋细胞上，但CACNB1也在T细胞中表达细胞，其在免疫反应中的作用仍然未知。最近，两种成孔物质的遗传学研究电压门控钙通道亚基和几个调节亚基已显示出 T 的功能改变缺乏这些通道亚基或表达突变形式的细胞。特别是监管的突变据报道，CACNB2、B3 和 B4 基因影响胸腺中 T 细胞的发育和胸腺中的稳态。脾。尽管 CACNB1 是 T 细胞中表达最高的，但其在 T 细胞中的作用尚未得到研究。 T 细胞中的四个调节亚基。总体而言，电压门控钙通道在 T 细胞和免疫反应仍然存在争议，部分原因是它们在 T 细胞中的激活机制尚不清楚，是不可电激发的。我们最近在活体小鼠的功能基因组筛选中发现了 CACNB1 作为调节 T 细胞生长以响应小鼠病毒感染的几种离子通道之一。在这个应用中，我们建议进一步表征 CACNB1 在 T 细胞功能和免疫反应中的作用。具体来说，我们将研究 CACNB1 的缺失如何影响钙信号传导、钙通道功能和 T 细胞生长、产生免疫调节细胞因子和杀死病毒感染细胞的能力。此外，我们将通过感染 T 细胞的小鼠来研究 CACNB1 缺陷对感染免疫的影响细胞缺乏带有病毒的 CACNB1，并分析它们的免疫反应。拟议的研究将揭示新的阐明 T 细胞中 CACNB1 和电压门控钙通道的功能以及免疫反应。 CACNB1是T细胞中表达最高、特异性最高的调节亚基，可能代表一种新的调节亚基。治疗自身免疫和炎症的药物靶点。